Studies to explore the mechanism of action of antidepressants in patients and volunteers have expanded to incorporate new analytical and biochemical approaches. Highlights of the last year include: 1. New algorithms for relating neurotransmitter measures allow us to distinguish both depressed and schizophrenic patients from controls as well as treatment responders from nonresponders. These findings provide our first direct evidence that measures of neurtransmitter interactions in patients may be used to better understand drug action. 2. We find involunteers that chronic lithium "up-regulates" components distal to adrenergic receptors on platelets and lymphocytes without affecting other indices of nonadrenergic function, such as release or turnover. This provides direct support for a primary effect of lithium on signal transduction and suggests that it inhibitory influence is compensated in vivo. 3. Dose response studies on intravenous administration of the atypical antidepressant alprazolm have established the appropriate dose for a pharmacological challenge in man potently reducing ACTH and cortisol, stimulating GH and suppressing norepinephrine in plasma. 4. The selective alpha-2 antagonist, idazoxan, appears to be an effective antidepressant and is able to produce sustained increases in plasma norepinephrine without altering cardiovascular parameters. These findings necessitate a reinterpretation of previous studies on catecholamines.